Anti-angiogenesis therapy has benefited many patients with cancer; however, insufficient efficacy, intrinsic refractoriness, and development of resistance have significantly reduced the therapeutic benefits of these therapies. Various hypotheses were proposed to explain the resistance associated with the anti-angiogenesis therapies, none was proven adequately to explain the apparent refractoriness and development of resistance. There is also a major gap in our understanding of the molecular determinants of development of resistance and refractoriness to anti- angiogenesis agents. Given that a significant research and financial efforts were spent on the development of anti- angiogenesis drugs, understanding the modes and mechanisms of resistance to anti-angiogenesis warrants further investigation. We have recently identified lysine methylation, a novel and previously unrecognized posttranslational modification that promotes kinase activation of VEGFR-2. Preventing methylation of VEGFR-2 on a specific lysine 1041 (K1041) residue inhibited VEGFR-2 mediated angiogenesis in cell culture, zebrafish and tumor growth in mouse. Our preliminary data demonstrates that the methylation of VEGFR-2 is associated with refractoriness and development of resistance to certain cancer therapies. Based on our recent published and data presented in the current application, we propose to investigate role of methylation of VEGFR-2 in de novo resistance to anti- angiogenesis therapy. The following specific aims are proposed to test our hypothesis. (A) Examine the hypothesis that methylation of VEGFR-2 is responsible for refractoriness and development of resistance to certain cancer therapies. Various mouse and zebrafish models will be used to examine role of methylation of VEGFR-2 resistance to anti-angiogenesis therapies. (B)Determine methylation status of VEGFR-2 in human colorectal cancer and correlate with responsiveness to angiogenesis inhibitors. There is an unmet need for effective anti-angiogenesis therapies. Establishing a link between methylation of VEGFR-2 and resistance/refractoriness to anti-angiogenic therapies could lead to a new class of cancer therapy and could overcome refractoriness and resistance to angiogenesis therapies.